1. Field of the Invention
This invention relates to bis-naphthalimides having heteroatom linkers, processes for their preparation, pharmaceutical compositions thereof, and various methods of using such bis-naphthalimides.
2. Description of the Related Art
Bis-naphthalimides have generally been useful in electrophotographic processes, as dyes, as fluorescent probes, in protein immobilization, in the stabilization of lipid bilayers or micelles, in organism death, for viral inactivation, for encapsulation and more recently in the treatment of cancer.
Bis-naphthalimides contain two naphthalimide groups joined by a linker and are generally synthesized by reacting two identical or different 1,8-naphthalic anhydrides with a bis-amine. The bis-amine may have internal alkyl or heteroatom groups which form the linker between the two naphthalimide groups in the bis-naphthalimide. Known linkers include the following:
i) C.sub.4 -C.sub.10 alkyl interrupted by one or two secondary or tertiary amino groups and two amino groups may be connected by an alkyl group, (U.S. Pat. No. 4,874,863, incorporated by reference herein); PA1 ii) connected in order: C.sub.2 -C.sub.5 alkyl; quaternary amine or nitrogen substituted cyclohexyl; methylene, methylene-carbonyl, methylene-amide, or methylene-amide-methylene; benzyl or dibenzyl coupled by methylene, isopropylene, oxygen or sulfur dioxide; this half of the linker is then repeated in reverse order for the other half of the linking group (U.S. Pat. No. 4,841,052, incorporated by reference herein); PA1 iii) connected in order: alkyl or derivatized alkyl; carbonyl or thiocarbonyl; tertiary amine; --(CH.sub.2).sub.n --n is 0 or 2-12; tertiary amine; carbonyl or thiocarbonyl; alkyl or derivatized alkyl (U.S. Pat. No. 5,206,250, incorporated by reference herein); PA1 iv) connected in order: C.sub.2 -C.sub.10 alkyl, tertiary amine, C.sub.2 -C.sub.10 alkyl, tertiary amine, C.sub.2 -C.sub.10 alkyl (U.S. Pat. No. 5,086,059, incorporated by reference herein); PA1 v) connected in order: alkyl; tertiary amine; alkyl; tertiary amine; alkyl (DMP840 is an example,U.S. Pat. No. 5,206,249, incorporated by reference herein); PA1 vi) combinations of unsaturated or saturated alkyl, fluorinated alkyl, alicyclic, aryl derivatives thereof, substitutions thereof, groups capable of complexing a metal ion, and biomolecules (U.S. Pat. No. 5,235,045, incorporated by reference herein); and PA1 vii) connected in order: propylene, secondary amine, butylene (Chen et al., 1993).
Current treatment methods for cancer, including radiation therapy, surgery, and chemotherapy, are known to have limited effectiveness. For example, breast cancer kills tens of thousands of people annually in the United States, the number being surpassed only by lung cancer deaths. Even with the implementation of educational programs designed to curb smoking and eating habits, cancer mortality rates will remain high well into the 21st century. The morbidity and mortality associated with cancer is exacting an ever increasing financial toll on an already overburdened health system. The development of new therapeutic compounds for the treatment of cancer is, therefore, a very important goal.
DNA intercalating agents are one of the most widely used classes of cancer chemotherapeutic agents currently used for the management of human cancers. Doxorubicin and daunorubicin are anthracycline antibiotics that intercalate with DNA. Although they differ slightly in chemical structure, daunorubicin has been used primarily in the acute leukemias, whereas doxorubicin has broader activity against human neoplasms, including a variety of solid tumors. The clinical value of both agents is limited by an unusual cardiomyopathy (Calabresi and Chabner, 1990). Several intercalators, including amsacrine (Denny, 1983), mitoxantrone (Cornbleet, 1984), and the anthrapyrazole DuP 941 (Talbot, 1991) have been reported to exhibit clinical anti-tumor activity. The DNA intercalator amonafide, a mono-naphthalimide, was reportedly shown to inhibit topoisomerase II and to result in intercalator-stabilized-topoisomerase II-DNA clearable complex formation (Hsiang et al., 1989).
Bousquet et al. (1993) reported cytotoxic activity in vitro and in vivo for certain bis-naphthalimides and Brana et al. relate to certain bis-naphthalimides having activity on a broad spectrum of human cancer cell lines. Chen et al. (1993) describe the synthesis of a bis-naphthalimide, XB596, having the linker--(CH.sub.2).sub.3 --NH--(CH.sub.2).sub.4 --. This compound reportedly demonstrated in vivo anti-tumor activity against MX-1 human breast carcinoma and DLD-2 human colon adenocarcinoma. However, its poor water solubility (45 mg/l) precluded further development (Sun et al., 1993).
DMP840, (R,R)-2,2'[1,2-ethanediylbis[imino (1-methyl-2,1-ethanediyl)]]-bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-d ione]dimethanesulfonate, is in phase I clinical trials (Sun et al., 1993; Papp et al., 1993; Czerniak et al., 1993; Arthaud et al., McRipley et al., 1993; Stafford et al., 1993). It has a reported water solubility of 3.4 g/l, anti-tumor efficacy in vivo, in particular against solid tumor xenografts, human and murine leukemia, doxorubicin resistant cell lines, colon carcinoma cells, early- and up-staged MX-1 mammary tumors, DLD-2 colon tumors, LX-1 lung carcinoma with no irreversible toxicities.
Although many of the compounds described above have general anti-cancer properties, most are ineffective against melanoma; in particular, the bis-naphthalimide, XB596, is ineffective against B16 melanoma (Chen et al., 1993)